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Annals of Surgical Oncology

, Volume 22, Supplement 3, pp 1402–1409 | Cite as

Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma

  • Hidenari Hirata
  • Keishi Sugimachi
  • Yusuke Takahashi
  • Masami Ueda
  • Shotaro Sakimura
  • Ryutaro Uchi
  • Junji Kurashige
  • Yuki Takano
  • Sho Nanbara
  • Hisateru Komatsu
  • Tomoko Saito
  • Yoshiaki Shinden
  • Tomohiro Iguchi
  • Hidetoshi Eguchi
  • Kazushige Atsumi
  • Katsumi Sakamoto
  • Toshiro Doi
  • Masakazu Hirakawa
  • Hiroshi Honda
  • Koshi MimoriEmail author
Translational Research and Biomarkers

Abstract

Background

Downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in cancers. The purpose of this study is to clarify the role of PRRX1 expression in predicting prognosis and mediating CSC-like properties in hepatocellular carcinoma (HCC).

Methods

The association between PRRX1 expression and overall survival (OS) of patients with HCC was analyzed in three independent datasets: 62 resected primary cases, 242 cases from GSE14520, and 162 cases from The Cancer Genome Atlas (TCGA). A cell line expressing PRRX1 (HuH7) was established for the functional analyses. The ability to form spheres, the expression levels of the hepatic CSC surface markers (CD13, CD133, and EpCAM), in vitro chemosensitivity to 5-fluorouracil (FU), and radiosensitivity were evaluated.

Results

Univariate and multivariate analyses showed that the 5-year OS of the low PRRX1 expression group was significantly poorer than that of the high PRRX1 expression group (P = 0.024 and P = 0.045, respectively). Consistent with this, the low PRRX1 expression group in GSE14520 and TCGA datasets showed significantly shorter OS (P = 0.027 and P = 0.010, respectively). Gene set enrichment analysis on GSE14520 and TCGA datasets indicated that downregulation of PRRX1 was correlated with the stemness signature. The number of spheres and the expression levels of CSC markers were significantly decreased when PRRX1 was expressed. Moreover, PRRX1 impaired resistance to 5-FU and radiation.

Conclusions

Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.

Keywords

Overall Survival Cancer Stem Cell HuH7 Cell Growth Inhibitory Assay Lung Squamous Cell Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

The authors thank K. Oda, K. Kasagi, S. Kohno, T. Kawano, M. Aoyagi, and J. Takano for technical assistance. This work was supported in part by the Funding Program for Next Generation World-Leading Researchers (LS094) and Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research, Grant numbers 24592005.

Disclosure

All authors have nothing to disclose.

Supplementary material

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References

  1. 1.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674-87.PubMedCrossRefGoogle Scholar
  2. 2.
    Haraguchi N, Ishii H, Mimori K, et al. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120:3326-39.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY. CD133 + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene. 2008;27:1749-58.PubMedCrossRefGoogle Scholar
  4. 4.
    Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136(3):1012-24.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Sugimachi K, Tanaka S, Kameyama T, et al. Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res. 2003;9:2657-64.PubMedGoogle Scholar
  6. 6.
    Ocana OH, Corcoles R, Fabra A, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012;22:709-24.PubMedCrossRefGoogle Scholar
  7. 7.
    Takahashi Y, Sawada G, Kurashige J, et al. Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer. Br J Cancer. 2013;109:307-11.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ieta K, Ojima E, Tanaka F, et al. Identification of overexpressed genes in hepatocellular carcinoma, with special reference to ubiquitin-conjugating enzyme E2C gene expression. Int J Cancer. 2007;121:33-8.PubMedCrossRefGoogle Scholar
  9. 9.
    Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1:2315-9.PubMedCrossRefGoogle Scholar
  10. 10.
    Roessler S, Jia HL, Budhu A, et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010;70:10202-12.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545-50.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mizuno H, Kitada K, Nakai K, Sarai A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med Genomics. 2009;2:18.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Natsume A, Ito M, Katsushima K, et al. Chromatin regulator PRC2 is a key regulator of epigenetic plasticity in glioblastoma. Cancer Res. 2013;73(14):4559-70.PubMedCrossRefGoogle Scholar
  14. 14.
    Sun T, Zhao N, Zhao XL, et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2010;51:545-56.PubMedCrossRefGoogle Scholar
  15. 15.
    Dang H, Ding W, Emerson D, Rountree CB. Snail1 induces epithelial-to-mesenchymal transition and tumor initiating stem cell characteristics. BMC cancer. 2011;11:396.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology.2007;132(7):2542-56.PubMedCrossRefGoogle Scholar
  17. 17.
    Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-60.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang Y, Zheng L, Huang J, et al. MiR-124 Radiosensitizes Human Colorectal Cancer Cells by Targeting PRRX1. PloS One. 2014;9(4):e93917.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Chen Y, Yu D, Zhang H, He H, Zhang C, Zhao W, Shao RG. CD133(+)EpCAM(+) phenotype possesses more characteristics of tumor initiating cells in hepatocellular carcinoma Huh7 cells. Int J Biol Sci. 2012;8:992-1004.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.PubMedCrossRefGoogle Scholar
  21. 21.
    Polo JM, Anderssen E, Walsh RM, et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012;151:1617-32.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Yang CS, Lopez CG, Rana TM. Discovery of nonsteroidal anti-inflammatory drug and anticancer drug enhancing reprogramming and induced pluripotent stem cell generation. Stem Cells. 2011;29:1528-36.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Hidenari Hirata
    • 1
    • 2
  • Keishi Sugimachi
    • 1
  • Yusuke Takahashi
    • 1
    • 3
  • Masami Ueda
    • 1
  • Shotaro Sakimura
    • 1
  • Ryutaro Uchi
    • 1
  • Junji Kurashige
    • 1
  • Yuki Takano
    • 1
  • Sho Nanbara
    • 1
  • Hisateru Komatsu
    • 1
  • Tomoko Saito
    • 1
  • Yoshiaki Shinden
    • 1
  • Tomohiro Iguchi
    • 1
  • Hidetoshi Eguchi
    • 1
  • Kazushige Atsumi
    • 2
  • Katsumi Sakamoto
    • 2
  • Toshiro Doi
    • 4
  • Masakazu Hirakawa
    • 2
  • Hiroshi Honda
    • 5
  • Koshi Mimori
    • 1
    Email author
  1. 1.Department of SurgeryKyushu University Beppu HospitalBeppuJapan
  2. 2.Department of RadiologyKyushu University Beppu HospitalBeppuJapan
  3. 3.Department of Gastroenterological Surgery, Graduate School of MedicineOsaka UniversitySuitaJapan
  4. 4.Department of Orthopedic SurgeryKyushu University Beppu HospitalBeppuJapan
  5. 5.Department of Clinical Radiology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

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